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Dr. Claudia dos Santos, Saint Michael’s Hospital
Exploiting Gene Expression Profiles to Decouple Biomolecular and Biophysical Injury in Animal Models of Ventilator Induced Lung Injury: The Role of Raf Kinase and Related Transcription Factor ATF3
Acute Respiratory Distress Syndrome (ARDS) is a life threatening form of injury to the lung. It can happen to anyone who is exposed to a significant trigger, and this can be as simple as the common cold or as complicated as multiple traumas following a serious car crash. When ARDS is triggered, lung cells release inflammatory mediators that lead to increase lung edema and results in failure to gas exchange. Because patients can no longer oxygenate, they require life support in the form of mechanical ventilation (MV). Despite medical advances the mortality from ARDS is high (34 to 65%) and serious morbidity can ensue following prolonged ICU stay in survivors. Currently there are no mediations available to treat ARDS, and although MV is life saving, it can lead to more life threatening complications termed ventilator induced lung injury (VILI). This apparently occurs because humans are not built to withstand air being pushed into the lungs by a machine. If we could prevent the mechanical injury or help the lungs withstand positive pressure ventilation we may be able to prevent deaths related to VILI. Because VILI begins as soon as patients are placed on the ventilator it is theoretically possible to anticipate the onset of VILI and unlike other syndromes treat quickly so as to avoid unnecessary deaths.
To achieve this, we need to understand what makes VILI (mechanical injury) different from other types of lung injury (chemical and molecular injury). To do this is complicated because on the surface, VILI can look exactly like ARDS. At the molecular level however, mechanical injury may have a very unique signature or profile. In this project I hypothesized that it may be possible to differentiate biochemical or molecular injury from mechanical injury based on pattern of gene transcription individual stimuli generate, and use this signature difference to pick out genes that are important in VILI. To do this, I have stretched cells in vitro, alone or in combination with chemical/molecular stimulants, and have looked at the molecular signature (gene expression profile) of genes that are regulated by mechanical stretch. I then used a bioinformatics approach to identify stretch regulated genes and the genes which in turn regulate them. To show that the genes that I think are regulated by mechanical force in-vitro are important in-vivo, I developed animal models that try to mimic ARDS and VILI and manipulated them in-vivo; and I inhibit either pharmacologically (Raf kinase) or via functional gene deletion (ATF3) to try and ascertain that contribution of these two related molecules in VILI.
This is a proof of concept study and I selected two genes, one that encodes for an enzyme called Raf kinase that mediates an entire pathway of gene expression and the other, is transcription factor called activating transcription factor 3 that works in a module, collection of genes that share common regulators as well as expression profiles (Fig. 2). Both genes are important in regulating biologically relevant processes including inflammation, growth and cell death. Using animal models I show that you can inhibit VILI in-vivo. The major strength of this project is the combinatorial approach to dissecting out clinically relevant stretch signals. In future proposal cellular specific deletion or inhibition of these molecules may provide much insight into the contribution of different cells to lung injury by biophysical force. The other innovative aspect of this research proposal is that the study tried to use a molecule specific pharmacological inhibitors that have been approved for human use and that are currently being used in unrelated medical problems. This approach will perhaps facilitate and expedite transition to patient care. If the drug results in decrease VILI, it can be tested immediately for use in patients in ARDS. Because this project is designed to translate knowledge gained in the basic science filed to the clinical world, it is a translational biology project with a focus on developing novel therapeutic approaches for VILI and ARDS. It also opens the door to future insult specific and probably cell specific personalized medicine strategies for ARDS.
Dr. Sanjay Mehta, Lawson Health Research Institute, London Health Sciences Centre, University of Western Ontario
Human Pulmonary Microvascular Endothelial Cell Injury: Role of Neutrophil-Endothelial Cell Interactions
Acute lung injury (=ALI) is a severe inflammation of the lungs which is common, serious, and often fatal. ALI affects 10,000 Canadians annually, especially critically ill patients with severe infections, such as pneumonia and sepsis. The treatment of ALI is mainly supportive care, including antibiotics for infection, fluid management, oxygen and artificial/mechanical respiration. However, there is no actual treatment and no cure for ALI. As such, patients with ALI still have a 30-40% risk of death. Those that survive have very poor quality of life afterwards. In the normal lung, the smallest, microscopic blood vessels (=microvasculature) are vital to the major breathing function of the lungs, the exchange of oxygen and carbon dioxide. The innermost lining cells of these microscopic blood vessels (=endothelial cells, EC) are normally responsible for preventing the leak of fluid and protein (=edema) into the lung, and keeping the lung working well. In ALI, injury to these lung microvascular EC is believed to cause lung edema, or drowning of the lung. There has been very little research into EC injury directly in human cells to better understand human ALI.
The overall focus of our research is a better understanding of the mechanisms of blood vessels and lung inflammation in order to improve treatment of ALI. The objective of this project is to directly study and to better understand human microvascular EC injury in ALI. We will use a novel technique to isolate and purify microvascular EC directly from human lung. We can then grow and study these microvascular EC in test tubes (=in vitro), under the same conditions of inflammation and infection as in patients with ALI, using bacterial chemicals (=lipopolysaccharide, LPS) and other chemical molecules which cause inflammation (=cytokines). The mechanisms of EC injury in ALI will be addressed by: (a) exposing microvascular EC to white blood cells (=neutrophil) during stimulation with LPS or cytokines, and assessing how neutrophils stick to EC, how neutrophils travel between EC (=migrate), and how neutrophils injure EC; (b) treating microvascular EC with drugs to block various hormones and chemicals, in order to define the role of these molecules in EC injury.
Other research has focused on ALI. Many studies have looked at large blood vessels of whole lungs. There has been little work directly assessing the human lung microvasculature, which is central in ALI. As well, much research in EC biology has used EC isolated from large blood vessels. However, EC from large blood vessels are extremely different from microvascular EC. Thus, our approach to ALI, directly isolating and studying microvascular EC from human lung tissue, is unique in the research into human ALI. This proposal seeks a greater insight into blood vessel and EC injury in ALI in order to improve therapy for patients with ALI. This proposal is relevant to the mission of OTS in 3 ways. (1) ALI is a common and clinically important condition of the lungs, which contributes significantly to the death of Canadians, and is costly to the healthcare system. (2) there are no effective therapies for ALI. There is the strong possibility that the proposed research will lead to novel therapeutic approaches targeted to EC injury in ALI. This may make a difference in the burden of disease and risk of death in Canadians. (3)_EC injury is also critically important in many other human lung diseases, including COPD and pulmonary hypertension. The proposed research will study mechanisms of human EC injury, so that our work has great, broad relevance to many lung diseases.
Dr. Sharon Dell, The Hospital for Sick Children
Making the Link between Objective Measures of Airway Disease and Epidemiological Survey Data: Validation of the ISAAC Questionnaire in Toronto School Children
Most of our Canadian statistics about asthma in children come from questionnaires (e.g. ISAAC survey) that ask parents to report whether their child has ever had asthma. In contrast, Canadian asthma guidelines emphasize that physicians should use objective measures of airway disease to verify an asthma diagnosis. Public health and other health services programs rely on this data to estimate burden of disease in order to appropriately allocate services. In addition, it might be important to know what kind of asthma a child has in order to determine what treatment the children will respond to and whether or not he/she will outgrow their asthma. To date, no one has actually studied whether parental reported asthma is the same as specialist diagnosed asthma using objective measures of airway disease and what kinds of asthma Canadian children have.
The main objective of this study is to compare the ISAAC asthma case (parental report on questionnaire) to a specialist diagnosis of asthma using objective measures of airway disease outlined in the Canadian Asthma Consensus Guidelines. Secondary objectives include (1) determining how many children with asthma-related symptoms have undiagnosed asthma and (2) describing the type of asthma that Canadian children have. The recently assembled T-CHEQ cohort, a population-based sample of 5619 Toronto school children, will be used as the sampling frame. Two hundred children will be randomly selected and classified into 3 different groups: reported asthma, asthma-related symptoms without reported asthma and normal controls. Participating children will undergo a number of tests that are objective measure of airway disease, including spirometry (how hard and fast a child can blow), exhaled nitric oxide measurement (measures airway inflammation), methacholine challenge (measures the twitchiness of the airways) and allergy skin testing (measures whether they have atopy or allergy). This study is a necessary step in order to have a good understanding of the burden of asthma and the interpretation of Canadian asthma studies. It will be the first study of its kind in Canada and will be unique in the world in that data collected from this study will also be linked to health services use through each participant’s health card information and measures of airway inflammation will be obtained in addition to tests of lung function. The outcome of this project is a necessary intermediate step to answering many important lung health questions exploring the relationship between air quality, asthma and respiratory symptoms in childhood.
Dr. Mark Inman, McMaster University
The Role of Mast Cells in Sustained Airway Hyperresponsiveness
One of the main problems in asthma is that the breathing tubes are twitchier than in most people, making them more susceptible to narrowing, which causes wheezing and the associated discomfort with breathing. Using a mouse simulation of allergic asthma, we will determine the involvement of an important ‘allergy’ cell, the mast cell, in the development of a wheeze. This will help us to determine how important it might be to try and eliminate this cell in the human condition. We have many lung specimens stored from mice which have been exposed to allergen and were known to develop twitchy airways. We will observe the pattern of mast cell inflammation to see whether this reduces the degree of twitchiness caused by allergen exposure. The stimulation of asthma we have developed includes a long lasting period of twitchy airways or breathing tubes. This is not present in other stimulations in other labs. We and others feel that this is a crucial aspect of real asthma and will make our studies of the mast cell potentially very valuable in the development of new treatment. When patients with asthma use the best available drugs, they will have noticeable symptoms on at least half of the days they are studied. There are no drugs that are able to completely reduce mast cell numbers, so these studies may help in the development of a new and much needed method of treating asthma.
Dr. Diane Lougheed, Queen’s University
Clinical Relevance of Abnormal Symptom Perception in Asthma: A Prospective Cohort Study
Poor perception of asthma symptoms may be a risk factor for life-threatening asthma. We have shown individuals with poor perception of the overinflation of the lungs that occurs during an asthma attack are more obese, have a larger resting inspiratory capacity (more ‘room to breathe’), are less anxious and report having been admitted to intensive care units more commonly than individuals with normal symptom perception.
To determine whether over and under recognition of asthma symptoms is linked to poor patient outcomes, such as acute attacks and visits to hospital emergency departments, a group of asthma subjects (~125) will be tested to determine whether they have poor, normal or increased perception of lung overinflation during a stimulated asthma attack. They will be followed for 2 years. The risk of adverse outcomes such as severe attacks needing hospitalization will be determined. This will be the first study to attempt to determine the clinical importance of abnormal perception of lung inflation during asthma attacks. The findings may determine risk factors for near-fatal and fatal asthma attacks, which in turn may help decrease asthma deaths. Poor and over perception of asthma symptoms may be risk factors for life-threatening asthma. This research is directly in line with the Lung Association’s mission as it aims to improve the lung health and outcomes of individuals with asthma, by advancing our understanding of factors linked to asthma morbidity and mortality.
Dr. Roger Goldstein, West Park Healthcare Centre
Upper Extremity Training in COPD: short and medium term effects on dyspnoea, health-related quality of life, arm function and arm exercise capacity
Chronic obstructive pulmonary disease (COPD) is a common condition throughout Canada and the rest of the world. Patients with COPD often describe of breathlessness that makes it difficult for them to participate in physical activity. Specifically, patients often report shortness of breath when they use their arms from simple activities of daily living such as dressing, lifting and bathing. Exercise training has been shown to reduce breathlessness in people with COPD. Compared with studies that have looked at the effects of exercise using the leg muscles, studies that focus on training the arm muscles in people with COPD are sparse. Although earlier work shows that arm training increases arm exercise capacity, the effects on other measures such as breathlessness are not clear.
The objectives of this study are to: (i) develop a feasible and safe arm training program (ATP) for patients with COPD, (ii) examine the effects of this ATP on quality of life, arm function, arm exercise capacity and breathlessness and fatigue during activities of daily living and, (iii) examine the effects of ATP on breathing responses during arm exercises. Patients with COPD will be assigned by chance to either a treatment or control group. All patients in both groups will complete the 6-week pulmonary rehabilitation (PR) program that is well-established at our center (West Park). During this program all patients will complete leg exercises, such as walking or cycling, and receive education about how to best manage their disease. In addition to this PR program, the treatment group will complete a specific ATP involving overhead arm exercises and free weights. The control group will undergo a “sham” ATP consisting of finger exercises. Before and after the ATP we will collect measures of; (i) breathlessness during activities of daily living, fatigue and quality of life, (ii) arm exercise capacity, (iii) arm function, (iv) arm muscle force. During the tests of arm exercise capacity a special machine (breathing-gas analysis system) will be worn. Measurements will be compared between the treatment and control groups before, immediately after the ATP and also 3 months after completing the ATP.
Previous studies that have looked at the effects of an ATP in people with COPD on measures that are important to patients such as symptoms of breathlessness and fatigue are inconclusive. Furthermore, no study has investigated the medium term (3 months) maintenance of any improvements seen following completion of an ATP in COPD. Finally, only one study has looked at breathing responses before and after training. However, this study did not compare these changes with a control group. Therefore the study in this application is novel as it will address these gaps using the best possible study design. The findings of the proposed research will help health-care professionals develop a safe and feasible ATP to reduce breathlessness during many common activities of daily living for patients with COPD. This is important as breathlessness during activity is the most important factor that reduces quality of life in COPD patients.
Dr. Martin Stampfli, McMaster University
Impact of Cigarette Smoke on Immune Inflammatory Processes and Tissue Remodeling elicited by Common Environmental Allergens
Smoking-related diseases are one of the major causes of suffering and death in Canada and worldwide. It is well known that smoking is the main cause of lung cancer and the development of chronic obstructive pulmonary disease (COPD). The impact of smoking on asthma, however, is still poorly understood, despite the fact that 25% of asthmatic individuals smoke in Canada. There is clinical evidence that asthma is more difficult to treat in smokers, however, it is not understood why. The focus of our research is to understand why asthma is harder to treat in smokers. We will study the impact of smoking on lung inflammation and tissue pathology. We believe that the proposed studies will provide a better understanding of the impact of cigarette smoke on lung health and asthma, in particular. The proposed studies will be pursued in models of experimental asthma using a well-characterized cigarette smoke exposure system.
Our experimental approach allows us to study the impact of cigarette smoke alone or in combination with allergens on lung inflammation and tissue pathology. To achieve this, we use unique experimental tools that mimic human cigarette smoke and allergen exposure. We are the only research group within Ontario, and likely Canada, that has the expertise to pursue the proposed studies. The Ontario Lung Association is dedicated to improve respiratory health through medical research. The impact of cigarette smoking on allergic airway diseases such as asthma is still poorly understood. The proposed studies will further our understanding of allergen/host interactions in the context of cigarette smoke and provide novel insight into the pathogenesis of asthma.
Dr. John Granton, Toronto General Hospital
Skeletal Muscle Dysfunction in Idiopathic Pulmonary Arterial Hypertension
Pulmonary hypertension (PH) is a disease that involves the circulation of the lung. IT is a dreaded complication of several lung, heart and rheumatic diseases. Alternatively PH can occur on its own without any predisposing factors. In this form it typically occurs in young women. Essentially a progressive narrowing of the blood vessels as they travel through the lung occurs, leading to a reduction in blood flow and build up in pressure in the vessels that are locked. This in turn, leads to stress on the right sided heart chambers and eventually heart failure. Death occurs, on average about 2 years after diagnosis, unless treated. Patients with pulmonary hypertension experience severe restriction in their activity levels because of breathlessness, light headedness, fainting and swelling of their extremities and internal organs, as heart failure progresses. Some of the difficulty that these people experience may be related to muscle weakness. This weakness may occur from indirectly muscle damage and has been seen in some forms of heart failure (e.g. after a heart attack) but has not been evaluated in patients with pulmonary hypertension. If muscle damage is present it will lead to newer approaches to care including exercise and strength training, nutritional therapies and specific medications.
To determine if there are changes in the structure and function of the muscle in patients with PH, in addition we want to find out if there are alterations in metabolism of the muscle that may explain these findings. Finally we want to evaluate potential causes for these findings. We will take small biopsies of muscle from the thigh of patients with PH and compare these to healthy people. We will evaluate the structure and composition of the muscle in these patients through molecular techniques. We will try to determine if these changes correlate with severity of PH and the degree of disability that these patients have. At present there are no studies of muscle structure and composition in patients with PH. We will also be using very sophisticated molecular methods to characterize what is happening in the muscle of these patients.
Dr. John Peter McPherson, University of Toronto
The Role of Bclaf1 (Bcl-2 associated factor 1) in Lung Development
Various molecular ‘circuits’ control the growth and development of various cells in the development and maturation of lungs during gestation. Imbalances in these molecular ‘circuits’, particularly those that control the formation and growth of smooth muscle in the lung, have been implicated in several lung diseases including bronchopulmonary dysplasia, asthma and interstitial pulmonary fibrosis. This application proposes to examine Bclaf1, a gene we have identified as a regulator of smooth muscle lineage development in the neonatal lung of mice.
We will use mice deficient in Bclaf1 to determine how Bclaf1 directs the regulation of smooth muscle development in the lung. Mice deficient in Bclaf1 show an excess in smooth muscle cells in the lung just before birth. We will use various techniques to determine whether the excess of smooth muscle cells is due to increased ability of the smooth muscle cells to grow or divide, or whether the smooth muscle cells have lost the ability to undergo programmed cell death. We have found that Bclaf1 protein interacts with another protein known as 9G8, which is important for regulating genes through a process known as ‘pre-mRNA splicing’. We will examine whether Bclaf1 affects the ability of 9G8 to function in this process. The ability of Bclaf1 to regulate ‘pre-mRNA splicing’ may help to explain how this protein controls the ability of smooth muscle cells to grow and develop in lungs. Our laboratory is unique in having the availability of mice deficient in Bclaf1 to study its role in lung development.
Several pulmonary diseases have been found to have defects in the growth or loss of smooth muscle. Understanding how smooth muscle development is regulated in the lung may help us understand how this control is lost in lung diseases. The identification and characterization of genes such as Bclaf1 that control lung development may provide new opportunities for designing new and improved therapeutic strategies to treat pulmonary disease.
Dr. Marina Ulanova, Lakehead University
The Role of Syk in Acute Pulmonary Infection Caused by Pseudomonas Aeruginosa
The pathogenic bacteria Pseudomonas Aeruginosa causes severe lung disease in patients in intensive care units. Normal lung defense mechanisms in these patients are often damaged when they are maintained on mechanical ventilation. Almost ¼ of such patients will contract Pseudomonas since these bacteria are present everywhere in the environment. It is extremely difficult to treat this ventilator-associated lung injury because these patients are already critically ill and also because Pseudomonas has high resistance to antibiotics. Among those who contract this infection in intensive care units, 69% will die. While there continues to be poor understanding of why Pseudomonas Aeruginosa causes such severe lung disease, it appears critical to learn more in order to prevent the fatal outcome of the disease.
The lungs possess a complex defense system against various pathogenic microorganisms. The cells lining the surface of the airways play a critical role in such defense. These epithelial cells prevent the infectious process in normal individuals. The main objective of this project is to understand how the protective functions of epithelial cells are regulated, and what fails when the infection process caused by Pseudomonas develops. In this research we will focus on one specific molecule. While its role in lung epithelial cells is still unclear, it is known to be extremely important in defense mechanisms against infections in white blood cells. This molecule is called Syk which stands for “spleen tyrosine kinase”. To answer the question ‘What is the role of Syk in acute lung infection caused by Pseudomonas?’, we will use a number of modern techniques of molecular and cellular studies developed in the research laboratory at the Northern Ontario School of Medicine. The experiments will be performed using human cells maintained in the laboratory that mimic normal cells present in the lungs. For our experiments, we will use a laboratory strain of Pseudomonas Aeruginosa genetically modified to carry a fluorescent tag. We will study both the process of bacterial penetration into lung cells and cellular responses that are triggered by the bacteria. To address the role of Syk in the regulation of various processes of the interaction between bacteria and lung cell, we will use highly specific molecular and genetic tools to disturb the normal function of Syk. These tools will help understand the precise role of Syk in the infectious process.
Since Syk was discovered in lung epithelial cells, researchers have been puzzled by the role of this molecule in the lung. The idea that Syk can be important in lung defense mechanisms against Pseudomonas infection is absolutely novel. To address this question, we have developed advanced techniques to study the intimate interactions between the bacteria and the lung cells. Such techniques allow for in-depth understanding of molecular mechanisms that are responsible for either beneficial or deleterious outcomes of the bacterial infection. Both the knowledge acquired during the study and the technologies can be applied to study other important lung infections, such as those caused by pathogenic staphylococci and streptococci. The understanding of molecular mechanisms that determine the outcomes of lung infection caused by the bacteria Pseudomonas Aeruginosa will help develop new therapies to fight ventilator-associated lung injury, which is an extremely severe and often fatal lung disease. The knowledge acquired during this study will also help recognized a possibility of side effects of drugs based on inhibitors of Syk that are now proposed for treatment of various diseases, such as rheumatoid arthritis, allergy, and lymphoma, and are undergoing clinical trials. Their clinical application requires complete understanding of the role of Syk in lung defense mechanisms, and such knowledge at present is missing. Our study will substantially enhance present knowledge in this area.
Dr. Zhou Xing, McMaster University
Immunoreceptor DAP12: a Novel Critical Negative Regulator of Immune Activation and Immunopathology in Respiratory Influenza Viral Infection
The research proposal deals with lung flu virus infection. Acute lung flu infection is caused by influenza virus and it continues to be an important cause of sickness or even death particularly in children, elderly people and those with chronic disease in North America and elsewhere in the world. Like many other lung viral infectious diseases, often the clinical symptoms and tissue injury in the lung are caused by imbalanced or uncontrolled immune responses that attempt to contain or clear the virus from the lung. Much still remains to be understood as to why this is happening.
Our current research project aims to investigate the mechanisms that help the host to control the immune response that may damage the lung tissue in the course of acute lung flu virus infection. More specifically, we will study the role of a recently newly identified molecule or protein called DAP12 (DNAX activating protein of 12 kDA), that is on the surface of some of our immune cells. Unfortunately little is known about whether and how this molecule may play a role in host defense against lung flu virus infection. We have very recently obtained some evidence to indicate that this molecule is very important in this process as the laboratory animals that do not have this molecule in their immune system will die of lung flu virus infection within 2 weeks of time. Based on this preliminary observation and to deepen our understanding, in our current project we will use a mouse model of human lung flu virus infection to study in more detail the role of DAP in host defense against lung flue virus infection and its mechanisms. We will first examine the expression of DAP12 and associated receptors in the lung during acute flue virus infection; we will then examine what happens to the immune response in the lung if there is a genetic lack of this molecule; and finally we will investigate whether and how such dysregulated immune response causes severe lung tissue injury and death. The unique aspect of our project is that we are the 1st to have identified the critical role of this molecule, DAP12, in determining the level of lung inflammation and tissue injury during flu infection. Therefore, our research project will generate new knowledge to help understand why some people die of acute lung flue infection and may eventually lead to the development of novel therapeutic strategies to save more lives.
Dr. Michael Fitzpatrick, Queen’s University
Mandibular Movement During Sleep
This research project relates to a condition called obstructive sleep apnea that is caused by the throat becoming obstructed during sleep. One factor that may influence the tendency for the throat to obstruct during sleep is the position of the jaw but, to date, there is very little information available on how the jaw position changes during sleep. To measure how the jaw position changes (1) during different sleep stages and different body positions in normal subjects; (2) between older and younger healthy adults; and (3) between patients with obstructive sleep apnea and healthy normal subjects. After 3 years of working on this project, we have recently developed a new device capable of measuring jaw position during sleep. The device is capable of accurately tracking jaw movement in all three movement planes (Vertical, anterior to posterior, and side to side) simultaneously. The proposed experiments will examine whether the jaw position changes between one sleep stage and another, between one posture and another (supine versus lateral), and whether it changes with age and with the presence of obstructive sleep apnea. The results provide new knowledge of human physiology and new knowledge of the pathogenesis of obstructive sleep apnea.
This will be the first study to map jaw movement in all 3 movement planes simultaneously during sleep. It will provide a unique insight into normal upper airway physiology during sleep. It will also provide insight into the whether changes in jaw position occur during sleep that could contribute to upper airway collapse, and whether those changes in jaw position during sleep differ with age in adults, or differ between adults with obstructive sleep apnea versus those without obstructive sleep apnea. Obstructive sleep apnea syndrome is a very common condition affecting approximately 5% of Canadian adults. The condition is associated with a greatly increased risk of stroke, heart attack and death. It is also associated with an increased risk of motor vehicle and work-related accidents, and with symptoms of tiredness, unrefreshing sleep and sleepiness. Improved knowledge of the factors contributing to this disease are essential to improve the understanding and treatment of it. This project will contribute significantly to that goal.
Dr. Richard Horner, University of Toronto
Mechanisms Underlying Opioid-Induced Suppression of Breathing
Abnormal breathing especially during sleep is often observed when opioid drugs such as morphine or fentanyl are administered clinically, e.g., to alleviate acute, chronic or post-surgical pain. Indeed, the most serious side effect of opioid drugs is depression of breathing, an effect that is potentially lethal. Opioid drugs can depress breathing by decreasing the activity of those muscles that generate airflow into the lung such as the diaphragm. Opioids may also suppress breathing by causing narrowing or closure of the air passage in the throat, due to relaxation of those breathing muscles (e.g., the tongue) that normally keep this air passage open. However, the sites and mechanism of action of opioid drugs in the central nervous system that mediate these important effects on breathing are unknown, and to answer these questions is the objective of this project.
The aim of this research is to understand the mechanisms underlying opioid induced respiratory depression in awake and sleeping rats. We will determine which brain structure, chemicals and receptors mediate depression of breathing following opioids in wakefulness and sleep. Opioid drugs are in widespread clinical use for pain management, especially following surgery when patients also spend a significant amount of time in sleep. However, despite the well-known serious side effect of respiratory depression that is potentially lethal, the sites of action in the brain where opioid drugs suppress breathing are not known. We have developed a unique animal model to identify the key sites in the brain where opioid drugs may act to suppress breathing. To identify and determine the basic mechanisms underlying respiratory depression with opioid drugs is essential to develop new pharmacological approaches of pain management without secondary effect such as life-threatening respiratory depression humans.
All grants are awarded based on ranking by the national peer review process conducted by the Canadian Thoracic Society. Budget requests totaling $2,031,026.60. Funding was approved for 13 of the 38 applications to be distributed in descending order of priority, based on their calculated national percentile ranking.
Approved and Recommended for Funding (Alphabetically)
|Dr. Sharon Dell, Hospital for Sick Children
Making the Link Between Objective Measures Of Airway Disease and Epidemiological Survey Data: Validation of the ISAAC Questionnaire In Toronto School Children
|Dr. Claudia Dos Santos, University of Toronto
Exploiting Gene Expression Profiles to Decouple Biomolecular and Biophysical Injury in Animal Models of Ventilator Induced Lung Injury: The Role Of Raf Kinase and Related Transcription Factor ATF3
|Dr. Roger Goldstein, West Park Healthcare Centre
Upper Extremity Training in COPD: Short and Medium term effects on dyspnoea, health related quality of life, arm function and arm exercise capacity
|Dr. John Granton, University of Toronto
Skeletal Muscle Dysfunction In Idiopathic Pulmonary Arterial Hypertension
|**Dr. Richard Horner, University of Toronto
Mechanisms underlying Opioid-Induced Suppression of Breathing
| Dr. Mark Inman, Firestone Institute for Respiratory Health
The Role of Mast Cells in Sustained Airway Hyperresponsiveness
|Dr. Diane Lougheed, Queen’s University
Clinical Relevance of Abnormal Symptom Perception in Asthma: A Prospective Cohort Study
|Dr. John Peter McPherson, University of Toronto
The Role of Bclaf1 (Bcl-2 Associated Factor1) In Lung Development
|Dr. Sanjay Mehta London Health Sciences
Human Pulmonary Microvascular Endothelial Cell Injury: Role of Neutrophil-Endothelial Cell Interactions
|Dr. Martin Stampfli, McMaster University
Impact of Cigarette Smoke on Immune Inflammatory Processes and Tissue Remodeling Elicited By Common Environmental Allergens
|Dr. Marina Ulanova, Lakehead University
The Role of Syk in Acute Pulmonary Infection Caused by Pseudomonas Aeruginosa
|Dr. Zhou Xing, McMaster University
Immunoreceptor DAP 12: A Novel Critical Negative Regulator of Immune Activation And Immunopathology In Respiratory Influenza Viral Infection
** OLA/OTS Breathe New Life Award: The funds for the “Breathe New Life Award” are partly raised by the OTS members through the Top It Up! For Respiratory Research fund. This fund enhances the nationally reviewed and acclaimed Grant-in-Aid research competition and funds grants above and beyond the normal value of the GIA budget provided by the Ontario Lung Association (OLA).